M. Felicia Basilicata

Our group will move to the BMC in September 2025.

Genes, Chromatin and Rare Neurodevelopmental Disorders

Our laboratory investigates the complex interplay between genetic alterations, cellular homeostasis, and biological sex in rare neurodevelopmental disorders (NDD). We employ multidisciplinary approaches to understand disease mechanisms and identify potential therapeutic and diagnostic strategies for conditions with no interventional protocols.

Plasticity and Resilience of developmental processes

Despite the diverse etiology of rare neurodevelopmental disorders, many genetic mutations converge like light in a prism, refracting predominantly into neuronal vulnerabilities and immune dysfunctions. We use human disease models to investigate how these seemingly different genetic perturbations ultimately converge on similar developmental bottlenecks, utilizing adaptive mechanisms involving paralogue compensation (e.g. Sm proteins, MPRL) and metabolic rewiring. By understanding how diverse genetic causes converge on shared cellular responses, we ultimately aim to develop interventions that address the refracted outcomes rather than the numerous causative ‘entry points’.

Chromatin Dysfunction in NDD

Collectively 58 million people worldwide are diagnosed with rare neurodevelopmental disorders leading to intellectual disability and failure to thrive. The most enriched class of causative mutations are found in genes belonging to the chromatin machinery, exemplified by the Basilicata-Akhtar syndrome. We explore how chromatin factors extend beyond their gene-regulating roles to affect processes outside the nucleus. Our research examines the critical communications between the nucleus and other cellular compartments —plasma membrane, mitochondria, endoplasmic reticulum, and lysosomes. These organelle networks maintain cellular homeostasis and enable rapid responses to environmental changes through direct material exchange. When chromatin architecture is disrupted, it triggers cascading effects throughout various cellular compartments, compromising homeostatic molecular dialogues. How these diverse genetic disruptions converge on common neuronal dysfunctions, regardless of their upstream etiology, remains a hidden nexus that our research aims to illuminate.

Sex Chromosomes in Development and Disease

A striking feature of neurodevelopmental disorders is their pronounced sex bias, with males typically affected at least twice as frequently as females. This pattern exists alongside females generally exhibiting higher immune system activity and greater susceptibility to autoimmune conditions. In our laboratory, we study how biological sex influences embryonic development and disease progression through both genetic and hormonal mechanisms. We investigate X-chromosome inactivation escape mechanisms and their tissue-specific regulation, providing insights into sex-biased diseases. By understanding how sex chromosome dosage influences differential cellular responses, we aim to develop more personalized approaches to treating developmental disorders that account for male-female differences in pathophysiology.